Thrombopoietic activity of tyrosyl-trna synthetase polypeptides
a technology of tyrosyltrna and polypeptides, which is applied in the direction of enzyme stabilisation, peptide/protein ingredients, extracellular fluid disorder, etc., can solve the problems of palliative and non-specific methods, drastic and expensive methods, and previous efforts to utilize thrombopoietin, the primary biological mediator of thrombopoiesis, have failed in the clinic, so as to reduce pulmonary inflammation and pulmonary inflammation.
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example 1
Stimulation of Thrombopoiesis In Vivo
[0252]The effects of a tyrosyl-tRNA synthetase polypeptide on thrombopoiesis were measured in vivo. The tyrosyl-tRNA synthetase polypeptide utilized in the experiments described below is a C-terminal truncation that comprises amino acids 1-364 of the full-length human tyrosyl-tRNA. This C-terminally truncated polypeptide was fused to an eight amino acid C-terminal tag (365-L-E-H-H-H-H-H-H-372) (SEQ ID NO:5). The amino acid sequence of the full-length human tyrosyl-tRNA synthetase is set forth in SEQ ID NO:1.
[0253]To measure the effects of tyrosyl-tRNA synthetase polypeptides on thrombopoiesis, in a first set of experiments, mice were injected subcutaneously twice daily for seven days with 3 μg / kg of the C-terminally truncated tyrosyl-tRNA synthetase polypeptide. In a second set of experiments, mice were injected twice daily for seven days with 1, 3, and 10 μg / kg of the C-terminally truncated tyrosyl-tRNA synthetase polypeptide. In a third set of ...
example 2
In Vitro Measurements of Thrombopoiesis
[0256]Effects on thrombopoiesis may also be measured in vitro. Stem cells are treated in vitro with a tyrosyl-tRNA synthetase polypeptide of the invention to determine its effect on hematopoietic progenitors of the erythroid, myeloid and megakaryocte lineages using colony-forming cell (CFC) assays (e.g., inhibition, stimulation, toxicity, synergism with other cytokines, hematopoietic defects). In addition, CD34+ megakaryocyte progenitor cells are treated in vitro with a tyrosyl-tRNA synthetase polypeptide of the invention to monitor megakaryocyte expansion and differentiation (e.g., increase in number of progenitor cells, stimulation of differentiation, increase in polyploidy). Similar experiments are performed using bone marrow and spleen cells derived from mice treated with a tyrosyl-tRNA synthetase polypeptide.
example 3
Combination Therapy Stimulates Thrombopoiesis
[0257]To assess whether a tyrosyl-tRNA synthetase polypeptide of the present invention has a synergestic and / or additive effect on the proliferation and differentiation of megakaryocytes in vitro, CD34+ cord blood cells are grown in liquid culture medium in the presence of optimal or sub-optimal formulations of cytokines (StemCell Technologies, Vancouver), such as IL-11, and treated with increasing concentrations of a tyrosyl-tRNA synthetase polypeptide. Additivity or synergism can be determined by monitoring the growth and differentiation of the progenitor cells in the two formulation conditions.
[0258]Similarly, in a protocol comparable to that described in Example 1, mice are injected with a limiting amount of thrombopoietin and with increasing amounts of a tyrosyl-tRNA synthetase polypeptide and the effects of the combination therapy on thrombopoiesis in vivo can be determined by platelet and megakaryocyte counts. In addition, combinat...
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